Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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Phase 1b study with PEGylated human IL-10 (AM0010) with 5-FU and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.399 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 399-399 ◽

Cited By ~ 4

Author(s):

J. Randolph Hecht ◽

Aung Naing ◽

Gerald Falchook ◽

Manish R. Patel ◽

Jeffrey R. Infante ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

De Novo ◽

Single Agent ◽

Hematological Toxicity ◽

Phase 1B

399 Background: The benefit of adding nal-irinotecan or oxaliplatin to 5-FU in second-line therapy for PDAC is relatively small and it has been refractory to immune therapies. The success and the durability of immunotherapy is thought to depend on the activation and expansion of intratumoral, tumor specific cytotoxic CD8+ T cells which are absent in most PDACs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune stimulation and prolonged stable disease in PDAC patients (pts) with single agent AM0010 was recently presented. Irinotecan may eliminate cytotoxic T cells. Treatment with platinum or 5-FU may activate immune responses to cancer and AM0010 has synergistic anti-tumor function with both in preclinical models. In this phase 1b clinical study, the efficacy of AM0010 with FOLFOX was explored in patients with PDAC. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated daily with AM0010 in combination with FOLFOX (n=20). Tumor responses were monitored using irRC. Immune responses were monitored using analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Pretreatment samples were analyzed by IHC for tumor infiltration by CD8+ T cells. Results: G3/4 TrAEs included thrombocytopenia (55%), anemia (45%) and neutropenia (25%). There was no significant bleeding or febrile neutropenia. 16 pts had a objective tumor response assessment; 2 had an irCR, 1 an irPR, 10 had irSD. Eight remain on treatment, 2 for > 1 year. ORR was 15%, the DCR was 65%. The mPFS was 3.9 months. AM0010 increased serum Th1 cytokines and reduced mediators of chronic inflammation IL-23 and IL-17 and the immunosuppressive cytokine TGFb. AM0010 increased the number and proliferation of PD1+ activated CD8+ T cells and induced de-novo oligoclonal expansion of T cell clones without affecting total lymphocyte counts. Conclusions: AM0010 with FOLFOX is well tolerated with moderate hematological toxicity in patients with PDAC. The observed immune activation including CD8+ T cell activation and prolonged objective responses are encouraging and will be explored in a phase 3 trial starting in 2016.

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Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes

10.1101/2020.06.06.20123414 ◽

2020 ◽

Cited By ~ 9

Author(s):

Takehiro Takahashi ◽

Patrick Wong ◽

Mallory K. Ellingson ◽

Carolina Lucas ◽

Jon Klein ◽

...

Keyword(s):

Sex Differences ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Response ◽

Innate Immune ◽

Female Patients ◽

Cytokines And Chemokines ◽

Male Patients

AbstractA growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1-4. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with mild to moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines and chemokines including IL-8, IL-18, and CCL5, along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients’ age and was predictive of worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide important basis for the development of sex-based approach to the treatment and care of men and women with COVID-19.

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HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

Journal of Virology ◽

10.1128/jvi.01690-18 ◽

2019 ◽

Vol 93 (10) ◽

Cited By ~ 7

Author(s):

Hakim Hocini ◽

Henri Bonnabau ◽

Christine Lacabaratz ◽

Cécile Lefebvre ◽

Pascaline Tisserand ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Mononuclear Cells ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Hiv Replication ◽

Hiv Controllers

ABSTRACT HIV controllers (HIC) maintain control of HIV replication without combined antiretroviral treatment (cART). The mechanisms leading to virus control are not fully known. We used gene expression and cellular analyses to compare HIC and HIV-1-infected individuals under cART. In the blood, HIC are characterized by a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T cell activation gene expression. This balance that persists after stimulation of cells with HIV antigens was consistent with functional analyses showing a bias toward a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. Taking advantage of the characterization of HIC based upon their CD8+ T lymphocyte capacity to suppress HIV-infection, we show here that unsupervised analysis of differentially expressed genes fits clearly with this cytotoxic activity, allowing the characterization of a specific signature of HIC. These results reveal significant features of HIC making the bridge between cellular function, gene signatures, and the regulation of inflammation and killing capacity of HIV-specific CD8+ T cells. Moreover, these genetic profiles are consistent through analyses performed from blood to peripheral blood mononuclear cells and T cells. HIC maintain strong HIV-specific immune responses with low levels of inflammation. Our findings may pave the way for new immunotherapeutic approaches leading to strong HIV-1-specific immune responses while minimizing inflammation. IMPORTANCE A small minority of HIV-infected patients, called HIV controllers (HIC), maintains spontaneous control of HIV replication. It is therefore important to identify mechanisms that contribute to the control of HIV replication that may have implications for vaccine design. We observed a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T-cell activation gene expression in the blood of HIC compared to patients under combined antiretroviral treatment. This profile persists following in vitro stimulation of peripheral blood mononuclear cells with HIV antigens, and was consistent with functional analyses showing a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. These results reveal significant features of HIC that maintain strong HIV-specific immune responses with low levels of inflammation. These findings define the immune status of HIC that is probably associated with the control of viral load.

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Interdependencies of cellular and humoral immune responses in heterologous and homologous SARS‑CoV‑2 vaccination

10.22541/au.164040480.07315088/v1 ◽

2021 ◽

Author(s):

Luise Erpenbeck ◽

Moritz M. Hollstein ◽

Lennart Münsterkötter ◽

Michael Schön ◽

Armin Bergmann ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Booster Vaccination ◽

Interferon Γ ◽

T Cell Response ◽

Cellular Immune Responses ◽

Cellular Immune

Background: Homologous and heterologous SARS-CoV-2 vaccinations yield different spike protein-directed humoral and cellular immune responses. This study aimed to explore their currently unknown interdependencies. Methods: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received vaccination with homologous ChAdOx1 nCoV-19, homologous BNT162b2 or with heterologous ChAdOx1 nCoV-19/BNT162b2. We assessed humoral (anti-spike-RBD-IgG, neutralizing antibodies, avidity) and cellular (spike-induced T cell interferon‑γ release) immune responses in blood samples up to 2 weeks before (T1) and 2 to 12 weeks following secondary immunization (T2). Results: Initial vaccination with ChAdOx1 nCoV-19 resulted in lower anti-spike-RBD-IgG compared to BNT162b2 (70±114 vs. 226±279 BAU/ml, p<0.01) at T1. Booster vaccination with BNT162b2 proved superior to ChAdOx1 nCoV-19 at T2 (anti-spike-RBD-IgG: ChAdOx1 nCoV-19/BNT162b2 2387±1627 and homologous BNT162b2 3202±2184 vs. homologous ChAdOx1 nCoV-19 413±461 BAU/ml, both p<0.001; spike-induced T cell interferon-γ release: ChAdOx1 nCoV-19/BNT162b2 5069±6733 and homologous BNT162b2 4880±7570 vs. homologous ChAdOx1 nCoV-19 1152±2243 mIU/ml, both p<0.001). No significant differences were detected between BNT162b2-boostered groups at T2. For ChAdOx1 nCoV-19, no booster effect on T cell activation could be observed. We found associations between anti-spike-RBD-IgG levels (ChAdOx1 nCoV-19/BNT162b2 and homologous BNT162b2) and T cell responses (homologous ChAdOx1 nCoV-19 and ChAdOx1 nCoV-19/BNT162b2) from T1 to T2. Additionally, anti-spike-RBD-IgG and T cell response were linked at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. Conclusions: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T cell activation is unlikely to compensate for poor humoral responses.

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Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients

Blood ◽

10.1182/blood.v99.4.1442 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1442-1448 ◽

Cited By ~ 104

Author(s):

Susanne Auffermann-Gretzinger ◽

Izidore S. Lossos ◽

Tamara A. Vayntrub ◽

Wendy Leong ◽

F. Carl Grumet ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Hematopoietic Cell ◽

Steady Increase ◽

Cell Transplant ◽

Allogeneic Hct

Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance. Mature DCs are transferred with hematopoietic grafts and subsequently arise de novo. Little information exists about engraftment kinetics and turnover of this cell population in patients after allogeneic HCT. This study examined the kinetics of DC chimerism in patients who underwent matched sibling allogeneic HCT. T-cell, B-cell, and myelocytic and monocytic chimerism were also studied. Peripheral blood cells were analyzed at defined intervals after transplantation from 19 patients with various hematologic malignancies after treatment with myeloablative or nonmyeloablative preparatory regimens. Cell subsets were isolated before analysis of chimerism. Despite the heterogeneity of the patient population and preparatory regimens, all showed rapid and consistent development of DC chimerism. By day +14 after transplantation approximately 80% of DCs were of donor origin with steady increase to more than 95% by day +56. Earlier time points were examined in a subgroup of patients who had undergone nonmyeloablative conditioning and transplantation. These data suggest that a major proportion of blood DCs early after transplantation is donor-derived and that donor chimerism develops rapidly. This information has potential implications for manipulation of immune responses after allogeneic HCT.

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Faculty Opinions recommendation of T cell activation-associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1000986.13107 ◽

2001 ◽

Author(s):

Martin Hemler

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cell Activation ◽

T Cell Response ◽

Antibody Affinity

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Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001615 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001615

Author(s):

Rachel A Woolaver ◽

Xiaoguang Wang ◽

Alexandra L Krinsky ◽

Brittany C Waschke ◽

Samantha M Y Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Single Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Tcr Repertoire ◽

Underlying Mechanisms ◽

Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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A role for CD9 molecules in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.184.2.753 ◽

1996 ◽

Vol 184 (2) ◽

pp. 753-758 ◽

Cited By ~ 63

Author(s):

X G Tai ◽

Y Yashiro ◽

R Abe ◽

K Toyooka ◽

C R Wood ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Expression Cloning ◽

Wild Type ◽

Almost All ◽

Antigen Presenting ◽

Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

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Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14565 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14565-e14565

Author(s):

Amit Adhikari ◽

Juliete Macauley ◽

Yoshimi Johnson ◽

Mike Connolly ◽

Tim Coleman ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Mouse Model ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

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